A reference may be made to an unexamined published Japanese patent application No. JP 212497 and examined Japanese patent publication Nos. 66318 and 79353 reporting that a compound in which platinum is coordinated to 1,2-diamino cyclohexane has excellent antitumor effect and relatively high safety. These substances, however, have disadvantages in that their pharmacological effects and safety are not always satisfactory and their administration by injection are limited because of their low solubility in water.
The first report on cis-oxalato-trans-l-1,2-diaminocyclohexane platinum(II) known as oxaliplatin was published in the year 1976 (Y. Kidani et al.). The authors synthesised cis-dichloroplatinum(II) compounds with cis, trans-l and trans-d isomers of 1,2-diaminocyclohexane as ligands and tested against either L-1210 or P-388 in CDF1 mice. The results showed the complex with trans-l ligand highly active. The cis-platin administration causes number of side effects such as renal toxicity, blood toxicity, nervous toxicity and digestive organ toxicity. In order to decrease the toxicity of these complexes, they prepared the mixed ligand complexes with dicarboxylic acids. Since then a no. of patents have appeared for the synthesis of different platinum compounds including oxaliplatin.
Conventionally, the compounds of formula I are prepared by following steps: reacting K2PtX4 (x is Cl or Br) with a 1,2-cyclohexanediamine isomer to form an intermediate cis-dihalo1,2-diaminocyclohexane wherein, halo could be chloro or bromo; dissolving the intermediate thus obtained in water under boiling; adding thereto a solution of silver nitrate in an amount of twice the mol equivalent of the said intermediate compound; separating the resultant precipitate of silver chloride or bromide through filtration; and adding corresponding dibasic organic acid to the filtrate.
However, the compounds of formula I obtained through the herein above-mentioned process contain dihydroxoplatinum complex as an impurity. Additionally the compounds thus prepared also contain other impurities such as unreacted intermediate, by-products of the said intermediate such as partially reacted chloroaquo, diaquodinitrate and unreacted silver ion thereby reducing the quality of the desired compound. One of the reasons of these impurities is low solubility of the intermediate in water. Further, because of high volume of water used in the reaction to take care of low solubility of the intermediate compound cis-dihalo1,2-diaminocyclohexane, the resulting precipitated silver chloride or bromide goes in to solution making it difficult if not impossible to remove the same completely.
U.S. Pat. No. 5,585,511 describes a platinum complex, which is highly soluble in water and thus can be used for preparing injectable formulations for treating malignant tumour. The compound is prepared as follows: reacting 1,2-diaminecyclohexane platinum(II) complex with silver nitrate in an amount 1.8 to 2 moles per mole of the said platinum complex, then reacting the diaquo complex thus formed with carboxylic acid and alkali, the resulting nitrato compound, where only one nitrate group is replaced, is further treated with halide so as to replace nitrate by halo group. This is extension of conventional method there by getting water soluble value added compound.
The prior art, as known to the inventor additionally includes U.S. Pat. No. 5,290,961. This patent describes a process that obviates the problems posed by the conventional process as mentioned herein above. The process advocates addition of sodium or potassium iodide to the reaction mixture, prior to the addition of organic dibasic acid, to convert the unreacted silver ion and cis-dihalo1,2-diaminocyclohexane into their iodine compounds. On removal of these iodine compounds by simple filtration organic dibasic acid is added to obtain the title compound. The disadvantage is the requirement of large amount of water. Similarly nitrate being monovalent, the amount of silver nitrate required for the reaction will be on higher side.
U.S. Pat. No. 5,939,133 teaches use of deoxygenated water in all steps and substituting nitrogen or an inert gas for air in an operational environment to produce low oxygen content atmosphere. Alternately degassing of an operational environment is proposed to eliminate the possibility of direct oxidation of platinum compound.
This process requires stringent operational conditions thereby making a process cost intensive.
U.S. Pat. Nos. 5,420,319; 5,298,642 and 5,338,874 disclose oxaliplatin with high optical purity through optical resolution. According to the process of these inventions, the starting material is optically resoluted by high performance liquid chromatography (HPLC) to the desired level and then reacted with tetrahalogen platinum (IV) and equimolar silver oxalate followed by reducing to the title compound. Alternately silver oxalate is substituted by silver nitrate or sulfate. Under these conditions the complex thus obtained is further reacted with oxalic acid to produce cis-oxalato(transl-1,2-cyclohexanediamine) Pt(II) complex.
Very recently Debio Pharm S. A. has published a patent (Koji Okamoto et al, WO 03/004505) claiming the invention of oxaliplatin active substance with low oxalic acid content (not more than 0.08%) thereby obtaining a product with reduced toxicity. The process of this invention advocates preparing dichloro(trans-l-1,2-cyclohexanediamine)platinum(II) by reacting K2Pt(II)Cl4 with trans-l-1,2-cyclohexanediamine, then adding 1.6 equivalents in respect to said compound, silver nitrate, then optionally adding potassium or sodium iodide and adding active carbon under stirring, filtering and treating the filtrate with alkali metal salt of oxalic acid. The crystalline oxaliplatin thus obtained is purified by washing repeatedly with water having pH between 4.5-7.0.
This patent is modification of U.S. Pat. No. 5,290,961. The compound obtained has oxalic acid below detectable limits.